Saptarsi M. Haldar, an assistant professor in the School of Medicine at Case Western Reserve University, has won a $300,000 Individual Biomedical Research Award from The Hartwell Foundation to investigate a new approach to slow the progress of Duchenne muscular dystrophy (DMD) in children.
Haldar will study how a gene called Kruppel-like factor 15 (KLF15) can help reduce the pace of development of the disease in mouse models of DMD. He also will begin to look for novel compounds that activate the factor. He is the third faculty member at Case Western Reserve to receive a prestigious Hartwell award in the two years the university has competed for the award.
Each year, The Hartwell Foundation invites a limited number of institutions in the United States to hold an internal open competition to nominate candidates from their faculty who are involved in early-stage, innovative and cutting-edge biomedical research that has not yet qualified for significant funding from outside sources.
The Hartwell Foundation selects at least 10 individuals to receive an award, which provides research support for three years at $100,000 per year. Last year, Case Western Reserve was one of 12 institutions invited to participate in the Hartwell competition, and Saptarsi was one of 12 individuals to receive a Hartwell Individual Biomedical Research Award.
Duchenne muscular dystrophy is a deadly, genetic muscle-wasting disease that mainly affects boys starting between ages three and five, and leaves most unable to walk or breathe by their teens. The disease is caused by an absence of a gene called Dystrophin, which is thought to provide strength to muscle fibers and protect muscle from injury.
While labs around the world are trying to find ways to get Dystrophin into muscle cells of children with DMD, Haldar’s work does not focus on the Dystrophin gene. Rather, he plans to use The Hartwell Foundation Individual Biomedical Research Award to study metabolic dysfunction in Duchenne muscular dystrophy.
“The notion that abnormal muscle metabolism is a treatable component of this genetic muscle disease is not part of mainstream thinking in the DMD field,” he said, “but the insights gained from understanding the important role of KLF15 in skeletal muscle have led us down this exciting path.”
Haldar began studying how the gene, KLF15, plays an important protective role in heart muscle. He wondered if the factor has similar affects on skeletal muscle. His initial studies of the gene were more broadly related to heart disease, not DMD. At the time, there was very little known about how this gene worked in the heart.
“As heart muscle and skeletal muscle have similar properties, especially with regard to metabolism, we suspected that KLF15 might be important in skeletal muscle function as well,” he said.
Working with Professor of Medicine Mukesh Jain and other university researchers, Haldar demonstrated that KLF15 boosts muscle metabolism during exercise. In tests of endurance exercise capacity, mice that received an extra dose of the factor could run longer, while mice that lacked the factor suffered exaggerated muscle fatigue and had poor endurance.
“Because KLF15 levels increase during exercise, I wanted to know exactly how our bodies activate this important metabolic gene,” he said. “Our group here and others have discovered that it is actually a major class of our bodies’ own steroid hormones, called glucocorticoids, that boost levels of the gene.”
Through a literature search, Haldar learned that steroids were effective in treating primary muscle diseases. He also found that steroids have been in clinical use for DMD for more than 20 years, although the exact mechanism by which they work remains elusive.
Since KLF15 was found to be boost muscle performance, Haldar suspected that activation of this critical metabolic gene might actually reflect how steroids work in DMD. One major problem with steroid therapy, however, is its severe side effects, such as osteoporosis, cataracts, weight-gain and fluid retention.
“Understanding how steroids such as prednisone work in DMD will eventually help us develop improved drugs that can capture the beneficial effects of these compounds while sparing many of their severe side-effects,” stated Haldar.
Looking further into the relationship, Haldar discovered that in both patients with DMD and in mouse models of muscular dystrophy, KLF15 levels are excessively low.
“It could be that reduced levels of KLF15 and subsequent problems with muscle metabolism accelerate progression of this disease,” Haldar said. “If we can prove that restoring KLF15 levels improves the disease, our findings may change the way people think about DMD progression and pave the way for novel treatment approaches.
The two other Case Western Reserve faculty members who received Hartwell Individual Biomedical Research Awards in the last two years include:
- Jennell C. Vick, PhD, (2011) an assistant professor of psychological sciences, who is pursuing innovative therapeutic treatment for severe speech disorders in children. Her work involves animated three-dimensional visual feedback software.
- Jonathan E. Sears, MD, (2011) an associate professor of ophthalmology, who seeks to overcome the adverse effects of elevated life-saving oxygen following premature birth. The disorder is called Retinopathy of Prematurity and causes permanent blindness.
